This grant is a joint effort by two laboratories (USA & Switzerland) interested in the role of host resistance and endocrine interactions in aging. Dr. Pierpaoli has made the remarkable observation that treatment of C57BL/6 and other strains of mice with melatonin, or transplantation of the pineal gland of young mice to the thymus gland of old mice, restores certain immune functions and increases the maximum life span of mice over untreated or sham controls. This indicates that one or more basic aging processes are being interrupted and important physiological functions are being restored in old mice. Melatonin is a regulatory hormone whose levels have been linked to various cancers especially breast and prostate as well as to the functioning of the immune system (Pool, R. Electromagnetic Fields: The Biological Evidence. Science, 249:1378, 1990. The extension of life, we hypothesize is afforded by longer maintenance and/or general restoration of host immune defensive reflex responses and neuroendocrine interactions in the older mice treated with melatonin. Ghanta and Hiramoto will study in old mice whether the defensive reflex response is defective and whether or not this defect is due to the inability of the CNS to perceive conditioned stimulus (CS) signals or if the defect resides in the inability of NK cells to respond. Pierpaoli's studies will be focused on the neuroendocrine mechanisms which are responsible for restoration of immunity and longevity. It would be of vital importance to secure information on the neuroendocrine mechanisms by which melatonin exerts its favorable effects on old mice in restoring either CNS perception of environmental signals and immune resistance. These studies include studying the effect of pinealectomy on longevity, and the effect of pineal transplants from young donors to old recipients on alterations of immune reactivity, hormonal functions, and lipid metabolism. These studies are unique in that we know of no other laboratories in this country or abroad which are engaged in this approach to study the problems linked to aging.